Pharmaceutical Development with Focus on Paediatric formulations

1. Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

2. Pharmaceutical Development with Focus on Paediatric formulations Presented by: Dr A J van Zyl Technical Officer Head of Inspections HSS/PSM/QSM vanzyla@who.int

3. Inspections (PQ) In this presentation: • WHO pre-qualification programme and inspections • Norms and standards • Inspection activities • APIs • FPPs • BE studies • QC labs • Inspection findings • Summary and conclusion

4. www.who.int/prequal

5. Inspections Inspections Manufacaturers: APIs Excipients; Finished Products Clinical /Contract Research Organizations QC Laboratories Correctiveactions Correctiveactions Correctiveactions Compliance Compliance Compliance Prequalification

6. Pharmaceutical Development with Focus on Paediatric formulations Batch verification Batch verification Complaints . Batch verification Batch verification Complaints Batch verification Complaints Complaints Complaints Monitoring compliance Monitoring compliance Monitoring compliance Monitoring compliance Monitoring compliance

7. Pharmaceutical Development with Focus on Paediatric formulations • Complex situation

8. Pharmaceutical Development with Focus on Paediatric formulations Quality concerns • Several developing countries – some serious quality concerns in some cases • Also in developed countries • Weak implementation and enforcement of GMP and GCP • "Double standards" e.g. products for export

9. Assessment procedure - inspections • Team of inspectors for each inspection • WHO PQ inspector plus PIC/S member country plus local country inspector (observer) • Some cases – capacity building (recipient country) • APIs, Finished products, BE studies • GMP, GCP, GLP, GSP, GDP. . . • Preparation: • SMF • Product information • Inspection reports, complaints etc

10. Manufacturers: Normally over 3 days Covers all aspects of GMP Quality management, Quality assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel, Utilities (e.g. HVAC, water) . . . Also data verification (dossier) including stability data, validation (process), development batches and bio batches Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification Clinical sites: Normally over 2 days Covers all aspects of GCP and GLP Ethical considerations, Protocol, Volunteers etc Data verification Clinical part Clinic, Pharmacy and related areas, data verification Bio-analytical part Laboratory and data verification Statistical analysis Assessment procedure - inspections

12. Inspections Inspections Manufacaturers: APIs Excipients; Finished Products Clinical /Contract Research Organizations QC Laboratories Correctiveactions Correctiveactions Correctiveactions Compliance Compliance Compliance Prequalification

13. Pharmaceutical Development with Focus on Paediatric formulations Inspections GCP GMP GLP Manufacaturers: APIs Excipients; Finished Products Clinical /Contract Research Organizations GPNCL GPCRO GMP GPNCL QC Laboratories Correctiveactions Correctiveactions Correctiveactions Compliance Compliance Compliance Prequalification

14. Standards • International consultation process • The WHO Expert Committee – review and adopts • Executive Board • World Health Assembly • Printed in respective TRS and WHO web site

15. Prequalification Programme: Priority Essential Medicines USP BP Ph. Eur. Ph. Int.

16. Prequalification Programme: Priority Essential Medicines

19. Prequalification Programme: Priority Essential Medicines

20. New York Times 2007

21. Pharmaceutical Development with Focus on Paediatric formulations In this presentation: • WHO pre-qualification programme and inspections • Norms and standards • Inspection activities • Active Pharmaceutical Ingredients • Finished Products • Bio-equivalence studies • QC labs • Inspection findings • Summary and conclusion

22. Prequalification Programme: Priority Essential Medicines

23. Prequalification Programme: Priority Essential Medicines Inspections have to cover all aspects including: • Receiving of material through all stages (storage, sampling and testing, weighing, production, packaging, finished product testing, storage and release) • Utilities e.g. water and HVAC

24. Prequalification Programme: Priority Essential Medicines

25. Prequalification Programme: Priority Essential Medicines

26. Prequalification Programme: Priority Essential Medicines

27. Prequalification Programme: Priority Essential Medicines

28. Airflow Problems Air deflected off scale!

29. Prequalification Programme: Priority Essential Medicines Quality Risk Management Risk assessment Risk communication Risk control Risk review

31. Assessment procedure - inspections Know the process: E.g. for tablet production • Weighing – Sieving – Mixing – Granulation and drying – Milling – Blending – Compression – Coating – Packaging. • Also storage and in-process control • Specific aspects: temperature and relative humidity • Contamination; mix-ups • Premises; equipment; documentation; personnel; validation and qualification; personnel flow, material flow etc • Cleaning

32. Prequalification Programme: Priority Essential Medicines • India, China, Belgium, France, Canada, Malaysia, South Africa, Switzerland, United States, Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda . . . Findings: • Compliance in some cases • Non-compliance in many cases • Full inspection report reflecting observations • Corrective action – verified before final conclusion

33. Prequalification Programme: Priority Essential Medicines

34. Prequalification Programme: Priority Essential Medicines

35. Different products in the same area including penicillin Lack in maintenance Inappropriate layout and finishing Lack in validation and qualification utilities and processes Cross-contamination and mix-ups Falsification of data Inappropriate sampling of materials and lack of testing before use No proof of sterility of products including validation of equipment and process Not following stability protocol Cleaning validation lacking Prequalification Programme: Priority Essential Medicines

36. Prequalification Programme: Priority Essential Medicines GMP compliance – India • Review of 30 inspection reports for GMP • Manufacturers in prequalification interested in international supply • Assessed against WHO GMP • Period 2001 to 2004

37. Prequalification Programme: Priority Essential Medicines Average numbers of non-compliances observed per site in each year (2001-2004).

38. Prequalification Programme: Priority Essential Medicines First inspections - Number of non-compliances in each area

39. Prequalification Programme: Priority Essential Medicines APIs - ICH Q7 I. QUALITY MANAGEMENT • A. Principles (2.1)., B. Responsibilities of the Quality Unit(s) (2.2). • C. Responsibility for Production Activities (2.3). , D. Internal Audits (Self Inspection) (2.4). • E. Product Quality Review (2.5). • II. PERSONNEL • A. Personnel Qualifications (3.1)., B. Personnel Hygiene (3.2). • C. Consultants (3.3).

40. Prequalification Programme: Priority Essential Medicines APIs - ICH Q7 III. BUILDINGS AND FACILITIES • A. Design and Construction (4.1)., B. Utilities (4.2). • C. Water (4.3)., D. Containment (4.4). • E. Lighting (4.5)., F. Sewage and Refuse (4.6). • G. Sanitation and Maintenance (4.7). • IV. PROCESS EQUIPMENT • A. Design and Construction (5.1)., B. Equipment Maintenance and Cleaning (5.2). • C. Calibration (5.3)., D. Computerized Systems (5.4).

41. Prequalification Programme: Priority Essential Medicines APIs - ICH Q7 • VI. MATERIALS MANAGEMENT • A. General Controls (7.1)., B. Receipt and Quarantine (7.2). • C. Sampling and Testing of Incoming Production Materials (7.3). • D. Storage (7.4)., E. Re-evaluation (7.5). • VII. PRODUCTION AND IN-PROCESS CONTROLS • A. Production Operations (8.1)., B. Time Limits (8.2). • C. In-process Sampling and Controls (8.3). • D. Blending Batches of Intermediates or APIs (8.4)., E. Contamination Control (8.5).

42. Prequalification Programme: Priority Essential Medicines APIs – Deficiencies include: • Annual Product Review – lack in review • Insufficient qualification and validation • Failure to provide documented evidence of sufficient control of the warehouse where starting materials, semi-finished product as well as finished products (including returned materials) were stored. E.g.; • temperature and relative humidity (to be stored below 30 degrees Celsius), inappropriate use of devices to monitor, office type ACs used

43. Prequalification Programme: Priority Essential Medicines APIs – Deficiencies include: • No separation between batches of material to prevent any possible mix-up of batches, Insects in the area • Nitrogen used to flush materials - no samples taken and no quality control tests performed • There was no procedure (SOP) or record for the cleaning of the tank (ABC123) and transfer lines (TFL123) for AAA used during processing.

44. Prequalification Programme: Priority Essential Medicines GCP – Bio-equivalence studies • GCP and GLP recommendations • Also the additional recommendations to CROs • Problems experienced in developed and developing countries • Team of inspectors – clinical part and bio-analytical part

45. Prequalification Programme: Priority Essential Medicines Clinical Sites • Volunteer selection and participation • Ethics committee operations • Clinic and bio-analytical laboratory • Archives • Pharmacy • CRFs • Source data • including chromatograms, ECGs

46. Prequalification Programme: Priority Essential Medicines Example of findings in a Clinical Trial • Two patients reported as voluntarily withdrawals were already dead • Original CRFs disappeared • Though the patient had died 8 days before - continued entries for dosing and no ADE between visits • Entries in CRF for 46 visits every 2 wks after death. • Radiologist report described “No changes” - Autopsy record “calcified focus of TBC found in the top part of the right lung”

47. WHO Prequalification and Bio-equivalence studies Source data…

48. WHO Prequalification and Bio-equivalence studies Example • CRFs destroyed on site due to "monsoon" • CRFs destroyed in archives due to "fire" • CRO: "CRFs and source data (chromatograms) given to the sponsor"; Sponsor: " CRFs and source data (chromatograms) archived by the CRO"

49. WHO Prequalification and Bio-equivalence studies Example • Two of the ECGs shown to the inspectors, bearing different subject numbers and initials, were found to be identical. • Other ECGs bearing different subject numbers and initials appear to have been recorded from a single subject. Out of 95 ECGs copied by the inspectors, 43 appear to have been recorded from the same and single subject during a single session • E.g. Project XXX: • screening, subjects #01, 02, 04, 06, 07, 08, and 11, 14, 19, 22, 23, 24, 25; • follow-up, subjects #02, 03, 04, 05, 06, 07, 08, 09, 10, 11, 12, 13, 15, 16, 19, 20, 21, 22, 24; • E.g. Project YYY: • screening, subjects #01, 02, 06, 07, 08, 09, 10, 11, 12, 19, 20. • follow-up, subjects #01 to 07, 10, 12 to 16, 18, 19, 21, 23 to 27

50. Prequalification Programme: Priority Essential Medicines